The possibility that the endocrine pancreas may be controlled by a neurohormonal mechanism has been proposed in light of previously described peptides of hypothalamic origin which inhibit the release of insulin and stimulate the release of glucagon both in vitro and in vivo. In an effort to establish this concept, several lines of research are proposed. (a) A modest scale isolation of these peptides will be initiated to establish viable methods for later more extensive isolation and peptide analysis and to provide the active material for further physiological experiments. (b) Several animal models will be used to test not only the insulin release inhibiting (IRI) and glucagon releasing (GR) activity of purified hypothamic extract but also to determine their physiological importance by their ability to alleviate the syndromes associated with ventromedial hypothalamic lesions and with genetically obese and diabetic mice. Through this type of replacement therapy along with in vivo and in vitro screening of Sephadex column fractions prepared from the hypothalmi of the genetically defective mice, the physiological role of these peptides in the regulation of insulin and glucagon release and their relationship to the primary dysfunction in these forms of diabetes and obesity may be uncovered.